With the possible exception of allogeneic transplantation, multiple myeloma remains an incurable illness due to pan-resistance to cytotoxic agents. Unfortunately, most patients are ineligible for allogeneic transplantation due to advanced age, comorbid illness or extensive prior therapy. As such, novel approaches are needed to treat this disease. The objective of this proposal is to develop novel clinical treatments for myeloma by translating promising strategies from the laboratory into the clinic and to enable Dr. Huff to become an independent translational investigator in the field of multiple myeloma, included in this career development proposal is formal training in the theory and methods of clinical investigation working towards a Masters of Health Science degree at the Johns Hopkins School of Public Health and Hygiene concurrent with translational research initiatives in multiple myeloma. Clinical results suggest that the cytotoxic conditioning regimen used in allogeneic transplantation plays a limited role in controlling myeloma, while the immunologic anti-tumor effect associated with graft-versus-host appears to have strong anti-myeloma activity. As such, we are developing a new clinical trial, utilizing nonmyeloablative BMT for myeloma that will limit the toxicity of the conditioning regimen and highlight the allogeneic graft-versus-myeloma effect. Based on encouraging preliminary data from the laboratory, we plan to incorporate anti-myeloma vaccines into the post-transplant donor lymphocyte infusions that are a key component of non-myeloablative BMT. For many patients, even a nonmyeloablative allo BMT will not be possible. Thus, other treatment approaches are needed. Preliminary data from our laboratory suggest that cytokine-mediated differentiation is another possible strategy. There are a variety of growth factors and cytokines which have activity in myeloma. IL-6 appears to be the most important. Interferon- clearly has clinical anti-tumor activity in myeloma, although its role in the management of multiple myeloma remains controversial. Interferon's exact mechanism of action is unknown; one of its multiple effects, however, is an anti-proliferative activity through induction of a G1 cell cycle arrest. The net effect of growth factors and cytokines on malignant growth is determined by a balance of their pleiotropic effects on tumor cell self-renewal, survival, and differentiation. The preferential enhancement of tumor cell self-renewal and/or survival could hasten tumor progression; conversely, a predominant or selective induction of differentiation would exhaust the neoplastic clone. Our preliminary data demonstrate that agents, like interferon, that inhibit cell cycling preferentially enhance the differentiation effects of IL-6 against myeloma, as well as block its effects on tumor cell proliferation.